Glypican 3-specific Chimeric Antigen Receptor Expressing T Cells As Immunotherapy for Patients with Hepatocellular Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Number of Patients with Dose Limiting Toxicity
研究概览
简要总结
This study enrolls patients who have a type of cancer that arises from the liver called hepatocellular carcinoma. The cancer has come back, has not gone away after standard treatment, has spread outside of the liver or the patient cannot receive standard treatment. This research study uses special immune system cells called GLYCAR T cells, a new experimental treatment.
The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients.
Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. In preclinical studies, the investigators made several genes called a chimeric antigen receptor (CAR), from an antibody called GC33 that recognizes glypican-3, a protein found on almost all hepatocellular carcinoma cells (GPC3-CAR). This study will test T cells genetically engineered with a GPC3-CAR (GLYCAR T cells) in patients with hepatocellular carcinoma.
The GLYCAR T cells are an investigational product not approved by the Food and Drug Administration.
The purpose of this study is to find the biggest dose of GLYCAR T cells that is safe, to see how long they last in the body, to learn what the side effects are and to see if the GLYCAR T cells will help people with GPC3-positive hepatocellular carcinoma.
详细描述
A maximum of 30 subjects will participate in the treatment part of this study.
Up to 180ml of blood is collected from patients to grow the T cells. The T cells are grown and a retrovirus (a special virus that can carry the GPC3 CAR gene into the T cells) is used to genetically engineer them. After the CAR gene is put into the T cells, the investigators make sure that they are able to kill hepatocellular carcinoma cells in the laboratory.
LYMPHODEPLETION CHEMOTHERAPY:
Several studies suggest that the infused T cells need room to be able to proliferate and accomplish their functions and that this may not happen if there are too many other T cells in circulation. Because of that, participants will receive treatment with cyclophosphamide (Cytoxan) and fludarabine for 3 days before receiving the T-cell infusion. These drugs will decrease the numbers of the participants' own T cells before the investigators infuse the GLYCAR T CELLS.
WHAT THE INFUSION WILL BE LIKE:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histology-proven hepatocellular carcinoma (HCC) which is unresectable, recurrent and/or metastatic
- •Barcelona Clinic Liver Cancer Stage A, B or C
- •GPC3-positive HCC
- •Age ≥ 18 years
- •Karnofsky score ≥ 60% (See appendix I)
- •Life expectancy ≥ 12 weeks
- •Child-Pugh-Turcotte score <8
- •Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent
- •Exclusion Criteria
- •History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies).
- •History of liver transplantation
- •Known HIV positivity
- •Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
- •Severe previous toxicity from cyclophosphamide or fludarabine
- •Treatment Eligibility
- •Inclusion Criteria:
- •Histology-proven hepatocellular carcinoma (HCC) which is unresectable, recurrent and/or metastatic
- •Barcelona Clinic Liver Cancer Stage A, B or C
- •GPC3-positive HCC
- •Age ≥ 18 years
- •Life expectancy of ≥ 12 weeks
- •Karnofsky score ≥ 60%
- •Child-Pugh-Turcotte score < 8
- •Adequate organ function:
- •creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 ml/min
- •serum AST< 5 times ULN
- •total bilirubin < 3 times ULN for age
- •absolute neutrophil count > 500/microliter
- •platelet count > 20,000/microliter (can be transfused)
- •Hgb ≥7.0 g/dl (can be transfused)
- •Pulse oximetry >90% on room air
- •Recovered from acute toxic effects of all prior antineoplastic drugs before entering this study (including investigational drugs) based on the enrolling physician's assessment (if some effects of chemotherapy are expected to last long term, patient is eligible if meeting other eligibility criteria).
- •Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion.
- •Available autologous transduced T cell product
- •Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent
排除标准
- •Eligible for complete tumor resection or liver transplantation.
- •Pregnancy or lactation (for women at child-bearing age, birth control is required)
- •Hepatic encephalopathy
- •Uncontrolled infection
- •Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day)
- •Known HIV positivity
- •Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
- •History of liver transplantation
- •Heart failure of Class III-IV and / or C-D per NYHA Criteria
- •History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies)
- •Severe previous toxicity from cyclophosphamide or fludarabine
研究组 & 干预措施
GLYCAR T cells + Fludarabine and Cytoxan
GPC3-CAR (GLYCAR T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with hepatocellular carcinoma.
干预措施: Cytoxan (Drug)
GLYCAR T cells + Fludarabine and Cytoxan
GPC3-CAR (GLYCAR T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with hepatocellular carcinoma.
干预措施: GLYCAR T cells (Genetic)
GLYCAR T cells + Fludarabine and Cytoxan
GPC3-CAR (GLYCAR T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with hepatocellular carcinoma.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Number of Patients with Dose Limiting Toxicity
时间窗: 6 weeks
DLT will be defined as any of the following that may, after consultation with the FDA, be considered possibly, probably, or definitely related to the study cellular products. * Any Grade 5 event * Non-hematologic dose-limiting toxicity is any Grade 3 or Grade 4 non-hematologic toxicity that fails to return to Grade 2 within 72 hours * Grade 2 to 4 allergic reaction to CAR T cell infusion. * Hematologic dose limiting toxicity is defined as any Grade 4 hematologic toxicity that fails to return to Grade 2 or baseline (whichever is more severe) within 14 days. * Grade 3 and 4 expected reactions due to CRS and neurotoxicity are seen with the use of CAR-based immunotherapy. Grade 3 cytokine release syndrome (CRS) infusion reactions and neurologic toxicity will only be reported to the FDA if they fail to return to Grade 1 within 7 days. Grade 4 CRS and neurologic toxicities will be reported to the FDA in an expedited fashion.
Recommended Phase 2 Dose (RP2D)
时间窗: 2 years
The RP2D is based upon the review of all available data including safety, preliminary anti-tumor activity, and MTD.
次要结局
- Percent of Patients with best response as either complete remission or partial remission(6 weeks)
- Median T cell persistence(15 years)
研究者
Tannaz Armaghnay
Assistant Professor
Baylor College of Medicine